King's College Study: Anti-Depressants Can Help People with Physical Ills

Although ME/CFS is not the focus of this study, I think the outcome is relevant: folks with physical illness frequently get depressed, and treatment with anti-depressants can help. This does not mean the illness is psychiatric in origin, it just supports the mind/body connection.

Discussion
Using complete datasets (including unpublished data) and a substantially larger dataset of this type than has been previously reported, we find that the overall effect of new-generation antidepressant medications is below recommended criteria for clinical significance. We also find that efficacy reaches clinical significance only in trials involving the most extremely depressed patients, and that this pattern is due to a decrease in the response to placebo rather than an increase in the response to medication.

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So, Pharma will be looking for new markets for this class of med. (SSRI, SNRI) as they roll out new drugs to treat depression.

Despite this, the evidence does seem to be mounting up against SSRI antidepressants. Although previous studies seemed to show SSRIs were effective, recent work has suggested this might be due to a bias in the way research is reported (Turner et al., 2008). Studies which show no effect have a tendency to be 'filed' rather than being submitted for publication. This can result in a much more rosy picture being painted of a drug's effectiveness than is really the case.

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Given the high incidence of suicidal ideation, suicide, violence and other truly chilling side effects related to these medications, this is pretty stunning stuff.

I think the placebo effect is eloquent evidence of the mind/body connection.

That's a meta-analysis, (not original research), and that wasn't really what it said.

These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients.

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The problem with "major depressive disorder" is that it is thought to be a serious, organic type illness which shares many symptoms with mild or moderate "depression", a common reactive emotional state which most people go through at some point in their lives. Efficacy studies typically net the former type of patient, who benefit from pharmaceutical intervention. (Another meta-analysis points out the same problem.)

However, the criteria for measuring depression in studies is controversial, and doesn't mesh with what clinicians report as finding in their practices. It's possible the drugs are effective for people more moderate depression, but, they're being sorted incorrectly by the Hamilton Scale. That would definitely skew the data.

Because drug intervention is cheaper for insurance companies and more convenient for patients than talk therapy, they are seriously over prescribed. Because of the side effects they really should be reserved for the sickest patients.

It's also interesting that they found the placebo response to be so high with depression: 80% (the placebo response decreased as the severity of depression increased.) The King's college "study" was also a meta-analysis didn't show the same high placebo, so something odd is at play. They also included tricyclics (older generation anti depressants) which are also helpful in chronic pain, so that may have had some benefit too. Who knows?

Conclusions
Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

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And, further in the part you quoted:

What Do These Findings Mean?
These findings suggest that, compared with placebo, the new-generation antidepressants do not produce clinically significant improvements in depression in patients who initially have moderate or even very severe depression, but show significant effects only in the most severely depressed patients. The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication. Given these results, the researchers conclude that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective. In addition, the finding that extremely depressed patients are less responsive to placebo than less severely depressed patients but have similar responses to antidepressants is a potentially important insight into how patients with depression respond to antidepressants and placebos that should be investigated further.

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I think they are pretty unambiguous in their analysis of the data. Not that their analysis is, necessarily, correct. I also think they are making a distinction, or attempting to, between major depression and reactive depression and their conclusions address that very issue.

I agree with you, whole heartedly, that major clinical depression is a totally different beast from the sadness and unhappiness which enter any and every life.

And, yes, your take on the decreased placebo response in major depression is much more subtly nuanced than mine was. In fact, it argues against an easily manipulated mind/body connection as the efficacy of the placebo effect dropped off when it could be said with more certainty that the underlying illness was most likely biologically based. I stated that very clumsily but I'm sure you catch my drift.

I actually think they were ambiguous! I heard the story on NPR and the resulting discussion. Both the health reporter who did the story, and you, came away with the conclusion:

Koan said:

Recent studies have shown that commonly prescribed antidepressants are really no better than placebo in relieving depression.

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Let's look at the conclusion you bolded. I'm sorry if I'm being over explanatory and redundant! I'm not sure why you bolded it but I'll go ahead and explain what it means:

The findings also show that the effect for these patients seems to be due to decreased responsiveness to placebo, rather than increased responsiveness to medication.

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Right. So what this means is that as the more severe the patient, the less effective the placebo. The resposne didn't increase, but it doesn't mean the anti depressant is not effective. (The response actually drops off a bit.)

Here's a graph from the study (I embedded it because the link was to a clunky PDF):

So, the bottom part of the graph shows the way the patients were "rated" for depression, based on severity. A score of 19 means the patient is "severe", 23 means they are "very severe", and anything over 28 is the "most severe".

So, clinical significance comes into play when drug works a LOT better than placebo. So, placebos work as well or better up until you get to 20, and then they work better (but not significantly better) than placebo until you get to the very sickest patients, for whom they work very well.

Does it make sense now?

Again, I'm sorry if you already understood it and I'm overdoing the explaining!

Koan said:

In fact, it argues against an easily manipulated mind/body connection as the efficacy of the placebo effect dropped off when it could be said with more certainty that the underlying illness was most likely biologically based.

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I wish I knew more about the placebo effect. In the study they mentioned that placebo in pain medication was 50%, which seems really high to me. It would be interesting to see what it is in say, infection, or wound care. I do know that it might be low for CFS patients!

Given the small improvement even in the most severely depressed I think their conclusions (as I pasted above) make perfect sense and that SSRIs don't actually work "very well" for any patient group. They do, however, have some small effect for the most ill. The apparently large area of clinically significant difference is accounted for as much by failure of placebo as it is by success of drug - but it actually represents a very small improvement over baseline.

Given the small improvement even in the most severely depressed I think their conclusions (as I pasted above) make perfect sense and that SSRIs don't actually work "very well" for any patient group. They do, however, have some small effect for the most ill.

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Oh, you mean how well people actually improved? It's in the analysis:

Confirming earlier analyses [2], but with a substantially larger number of clinical trials, weighted mean improvement was 9.60 points on the HRSD in the drug groups and 7.80 in the placebo groups

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It's about a 30% reduction in symptoms for the very sick. Not a huge improvement, but to someone who is mentally incapacitated from depression, it probably means a lot. As a severely ill person with CFS, if there was a pill I could take to improve some functioning, I would be ecstatic.

SW is at King's College and they are desperately trying to get somatisation as part of physical illnesses, talk about trying to expand your empire. And cut down insurance payments for things like MS where people get them young and for life.

The people involved in this, Cochrane library, Hotopf are the ones who have made life hell for so many of us.

We all know how rigorous their research is. I wouldn't believe anything they say.

It's about a 30% reduction in symptoms for the very sick. Not a huge improvement, but to someone who is mentally incapacitated from depression, it probably means a lot. As a severely ill person with CFS, if there was a pill I could take to improve some functioning, I would be ecstatic.

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So would I, Robin! But, the 30% difference between 7.80 and 9.60 does not translate to a 30% reduction in symptoms, alas.

Mithriel,

So what do you think they're up to here? The discussion I linked to in my first post puts forth some interesting ideas.

I was just washed over with weariness. It doesn't matter what they're up to! They will be washed away by the clean waters of history soon enough!

I have been very interested in this subject for years now. Ever since I have had countless doctors trying to shove expensive antidepressants down my throat, and knowing from my own reading of the original placebo trials that they seemed to be no better than the placebos.

Then I read the analysis in the NEJM, which uncovered all the unpublished studies and showed what I already knew to be the case.

Just a couple points.
Robin wrote,

The problem with "major depressive disorder" is that it is thought to be a serious, organic type illness

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Some who stand to make a profit have made that claim, but no evidence has ever been produced that shows any depression to be a 'physical' disease. And given how much effort big pharma is surely putting in trying to make that case, I think the lack of evidence at this point is quite telling.

Also, regarding the placebo effect, one must also take into account the fact that SSRI's have noticeable side effects, which add to the probability of experiencing a placebo effect.

Basically, if you are taking the SSRI, you may get a headaches, or some other side effect. When you notice the headaches, you are convinced that you are taking the real drug and not the placebo, and that certainty leads to a higher likelihood of experiencing a placebo effect. There is a name for this phenomenon, I just can't think of it. But it would easily account for any slighty better performance of the SSRI, especially with the more severe cases.

So would I, Robin! But, the 30% difference between 7.80 and 9.60 does not translate to a 30% reduction in symptoms, alas.

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It actually does. The 30% I was referring to is the 9.60 reduction is in the overall HRSD score. So for 28s (most severe), the mean improvement in that group would be -9.6 with an antidepressant. On average their scores would go to an 18.4. Still depressed but not as badly. The placebo response is a very good one too: 7.8. So, if you were less severely depressed, you were more likely to respond to a placebo. If you were an 18, you might expect to lose 7.8 HRSD points on placebo -- experience a nearly 50% improvement.

It depends on the initial severity of symptoms -- who responds to the placebo and who responds to the drug. Like you said, it depends on what's actually wrong with the patient.

There is a problem with the issue of 'placebo'. RCTS on any drug do not measure a 'placebo EFFECT' - they measure a placebo RESPONSE. There is a subtle but essential difference. Basically 'placebo' is just nothing is done, and some people might still improve or recover. There may be other reasons for this. It’s not a real ‘effect’ at all but often a misattribution of some non-specific perceptions of effect when there is in fact none. The ‘placebo effect’ is equivalent to no effect at all – it isn’t due to some occult 'mind/body' effect, it doesn’t mean that the placebo 'benefits' some people. It actually means is that there is no measurable benefit whatsoever above giving nothing, when the drug under trial is no better or little better than 'placebo'. People often don't realise this- even Ben Goldacre can't get his head around this.

There are all sorts of reasons relating to fluctuation of conditions, 'regression to the mean' etc. including flawed methodology to explain why placebo may appear higher

Also 'placebo' response tends to be higher in conditions that rely on subjective reporting rather than objective measurement. 'Placebo' response has never, to the best of my knowledge, been high in RCTs for treatments for uncontested organic conditions.

I recently discovered on this forum that we are sometimes hyperserotonergic -- have high serotonin levels without medication. That would certainly fit with Cheney's observation of brain frying.

Many years ago I voluntarily took SSRIs in an attempt to increase energy (I was not depressed - it's not my thing, anxiety was my thing) when I had little information about ME and less about SSRIs. It was one of the biggest mistakes I've made in my life and, certainly, the single biggest mistake I've made during my illness.

I remember reading somewhere that Dr Cheney had said that antidepressants 'fry the brains' of ME/CFS sufferers, but do not have more details.

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Min, I read that, too. Cheney went on to say that using our brains did the same thing. His recommendation? Take klonopin and just veg out all the time. His reasoning is that it will save the brain cells and, consequently, our brains.

Brain drain is all too common in CFS. Hence, Koan's very much used Burnout Bench! Using one's thinking power is an energy usage like running around the block. Re: the term "brain ache."

I heard Nancy Klimas speak, and she said we are losing grey matter in our brains, and that actually they are getting smaller. Maybe following Cheney's advice would stop that.